DESCRIPTION Chronic pain symptoms are extremely common among Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans, and more than 50% of OEF/OIF Veterans report chronic pain symptoms upon return from deployment (low back pain being the most commonly reported). Unfortunately, pharmacological management of pain is frequently suboptimal, and many OEF/OIF Veterans experience persistent and unalleviated pain symptoms and/or intolerable side effects from pain medications. For example, current medications such as opiates are commonly used to treat chronic pain symptoms, but narcotic analgesics can have serious side effect risks such as respiratory depression, addiction, sedation, and potentially lethal interactions with other drugs. There is thus an acute and urgent need for the development of effective, safe, and non-habit-forming new pharmacological treatments for chronic pain disorders. Extensive preclinical data in rodent models and clinical findings in OEF/OIF Veterans suggest that neurosteroids may be promising therapeutic approaches for the treatment of pain disorders in OEF/OIF Veterans. Neurosteroids are endogenous molecules that are enriched in human brain and are immediately accessible for translation to clinical trials, as they are available over-the-counter as dietary supplements in the U.S. Neurosteroid interventions may thus represent an important new lead for the management of chronic pain symptoms in OEF/OIF Veterans. Based on our preliminary data in OEF/OIF Veterans and rodent data from multiple research groups demonstrating the analgesic actions of neurosteroids, our first objective is to conduct a randomized controlled trial (RCT) in 90 OEF/OIF Veterans with chronic low back pain to investigate if the neurosteroid pregnenolone is effective in alleviating pain symptoms in this cohort. This will be a 4-week, randomized, double-blind, placebo-controlled study, preceded by a one-week pain assessment period and a one-week placebo lead-in period. We hypothesize that treatment with pregnenolone will significantly reduce self-reported back pain and improve functional outcomes in OEF/OIF Veterans. Our second objective is to determine whether neurosteroid levels in serum can have utility as predictors of self-reported pain and response to neurosteroid intervention. We thus hypothesize that increases in neurosteroids post-treatment with pregnenolone will predict therapeutic response, as suggested by preliminary data in our prior pilot RCTs in Veterans with PTSD, schizophrenia, and mild TBI. Our third and exploratory objective is to determine if there is preliminary evidence for an association between common genetic variations in the enzymes involved in neurosteroid synthesis, serum concentrations of neurosteroids, and treatment response to a neurosteroid intervention. Significance: This project could lead to a novel therapeutic for OEF/OIF Veterans with chronic pain disorders that is safe, non-habit-forming, inexpensive, well-tolerated, and improves functional outcome and quality of life. It could also identify candidate biomarkers for therapeutic response, potentially leading to efficacious personalized treatments for Veterans with pain conditions. PUBLIC HEALTH RELEVANCE: There is currently a paucity of safe and effective agents for the treatment of chronic low back pain, a disorder that impacts large numbers of OEF/OIF Veterans and is frequently accompanied by PTSD and other comorbid symptoms. If pregnenolone, as a precursor loading strategy that can enhance or restore endogenous levels of allopregnanolone, can result in symptom reduction, pregnenolone could represent an effective, safe, well- tolerated, immediately accessible, and inexpensive treatment for these symptom domains, potentially leading to improved functional outcome and quality of life in OEF/OIF Veterans with chronic pain disorders.